3-Methylthiophene -Drug Synthesis Database

【结构式】

【分子编号】12442

【品名】3-Methylthiophene

【CA登记号】616-44-4

【分子式】C₅H₆S

【分子量】98.16864

【元素组成】C 61.18% H 6.16% S 32.66%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

The synthesis of 5-hydroxytiagabine, a metabolite of tiagabine in humans, has been undertaken to confirm that it is present entirely as (E)- and (Z)-isomers of the tautomeric 5-oxo form: The bromination of 3-methylthiophene (I) with N-bromosuccinimide gives 2-bromo-3-methylthiophene (II), which is chlorinated with N-chlorosuccinimide to yield 2-bromo-5-chloro-3-methylthiophene (III). The reaction of (III) with Mg affords 5-chloro-3-methylthien-2-ylmagnesium bromide (IV), which is condensed with 3-methylthiophene-2-carboxaldehyde (V) (obtained from (II) by reaction with magnesium and dimethylformamide) to give the bisthienylmethanol (VI). The oxidation of (VI) with pyridinium chlorochromate (PCC) yields the bisthienyl ketone (VII), which is treated with sodium methoxide to afford the bis(2-thienyl)ketone (VIII). The Grignard reaction of (VIII) with cyclopropylmagnesium bromide (IX) gives the trisubstituted methanol (X), which is submitted to ring opening with trimethylsilyl bromide to afford the thiophenone (XI) as a mixture of the (E)- and (Z)-isomers. The condensation of (XI) with piperidine-3(R)-carboxylic acid ethyl ester (XII) by means of K2CO3 gives 1-[4-(3-methyl-5-oxo-2,5-dihydrothien-2-ylidene)-4-(3-methyl-2-thienyl) butyl]piperidine-3(R)-carboxylic acid ethyl ester (XIII) (also as a mixture of (E)- and (Z)-isomers). Finally, this compound is hydrolyzed to the free acid in HCl medium.

参考文献中间体

合成目标

【1】 Thogersen, H.; Chorghade, M.S.; Lee, E.C.; Andersen, K.E.; Sorensen, P.O.; Lundt, B.F.; Begtrup, M.; Lau, J.; Petersen, H.; The synthesis of novel GABA uptake inhibitors. 2. Synthesis of 5-hdroxytiagabine, a human metabolite of the GABA reuptake inhibitor tiagabine. Tetrahedron 1994, 50, 29, 8699.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	12442	3-Methylthiophene	616-44-4	C₅H₆S	详情	详情
(II)	12443	2-Bromo-3-methylthiophene	14282-76-9	C₅H₅BrS	详情	详情
(III)	12444	2-Bromo-5-chloro-3-methylthiophene		C₅H₄BrClS	详情	详情
(IV)	12445	Bromo(5-chloro-3-methyl-2-thienyl)magnesium		C₅H₄BrClMgS	详情	详情
(V)	12446	3-Methyl-2-thiophenecarboxaldehyde; 3-Methyl-2-thiophenecarbaldehyde	5834-16-2	C₆H₆OS	详情	详情
(VI)	12447	(5-Chloro-3-methyl-2-thienyl)(3-methyl-2-thienyl)methanol		C₁₁H₁₁ClOS₂	详情	详情
(VII)	12448	(5-Chloro-3-methyl-2-thienyl)(3-methyl-2-thienyl)methanone		C₁₁H₉ClOS₂	详情	详情
(VIII)	12449	(5-Methoxy-3-methyl-2-thienyl)(3-methyl-2-thienyl)methanone		C₁₂H₁₂O₂S₂	详情	详情
(IX)	12450	Bromo(cyclopropyl)magnesium;cyclopropylmagnesium bromide;cyclopropylmagnesiumbromide	23719-80-4	C₃H₅BrMg	详情	详情
(X)	12451	Cyclopropyl(5-methoxy-3-methyl-2-thienyl)(3-methyl-2-thienyl)methanol		C₁₅H₁₈O₂S₂	详情	详情
(XI)	12452	5-[(E)-4-Bromo-1-(3-methyl-2-thienyl)butylidene]-4-methyl-2(5H)-thiophenone		C₁₄H₁₅BrOS₂	详情	详情
(XII)	12453	ethyl (3R)hexahydro-3-pyridinecarboxylate		C₈H₁₅NO₂	详情	详情
(XIII)	12454	ethyl (3R)-1-[4-[3-methyl-5-oxo-2(5H)-thiophenylidene]-4-(3-methyl-2-thienyl)butyl]hexahydro-3-pyridinecarboxylate		C₂₂H₂₉NO₃S₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIII)

Preparation of the racemic arylpropionic acid (IX) has been reported through a number of different procedures. 4-Aminoacetophenone (XI) was diazotized to (XII) employing isoamyl nitrite and either acetic or fluoboric acid. Then, the Gomberg-Bachmann coupling of diazonium salt (XII) with 3-methylthiophene (XIII) furnished 4-(3-methyl-2-thienyl)acetophenone (XIV). Subsequent Darzen's condensation of acetophenone (XIV) with methyl chloroacetate (II) afforded the glycidic ester (XV), which was further hydrolyzed to acid (XVI), and then decarboxylated to aldehyde (XVII). Oxidation of (XVII) to the key carboxylic acid was performed by treatment with potassium permanganate

参考文献中间体

合成目标

【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 .
【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	10257	methyl 2-chloroacetate; methyl chloroacetate	96-34-4	C₃H₅ClO₂	详情	详情
(IX)	62687	2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid		C₁₄H₁₄O₂S	详情	详情
(XI)	27847	1-(4-aminophenyl)-1-ethanone	99-92-3	C₈H₉NO	详情	详情
(XII)	62688	4-acetylbenzenediazonium		C₈H₇N₂O	详情	详情
(XIII)	12442	3-Methylthiophene	616-44-4	C₅H₆S	详情	详情
(XIV)	62689	1-[4-(3-methyl-2-thienyl)phenyl]-1-ethanone		C₁₃H₁₂OS	详情	详情
(XV)	62690	methyl 3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxiranecarboxylate		C₁₆H₁₆O₃S	详情	详情
(XVI)	62691	3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxiranecarboxylic acid		C₁₅H₁₄O₃S	详情	详情
(XVII)	62692	2-[4-(3-methyl-2-thienyl)phenyl]propanal		C₁₄H₁₄OS	详情	详情

Extended Information